Current advances in the use of exosomes, liposomes, and bioengineered hybrid nanovesicles in cancer detection and therapy

Abstract

Three major approaches of cancer therapy can be enunciated as delivery of biotherapeutics, tumor image analysis, and immunotherapy. Liposomes, artificial fat bubbles, are long known for their capacity to encapsulate a diverse range of bioactive molecules and release the payload in a sustained, stimuli-responsive manner. They have already been widely explored as a delivery vehicle for therapeutic drugs as well as imaging agents. They are also extensively being used in cancer immunotherapy. On the other hand, exosomes are naturally occurring nanosized extracellular vesicles that serve an important role in cell-cell communication. Importantly, the exosomes also have proven their capability to carry an array of active pharmaceuticals and diagnostic molecules to the tumor cells. Exosomes, being enriched with tumor antigens, have numerous immunomodulatory effects. Much to our intrigue, in recent times, efforts have been directed toward developing smart, bioengineered, exosome-liposome hybrid nanovesicles, which are augmented by the benefits of both vesicular systems. This review attempts to summarize the contemporary developments in the use of exosome and liposome toward cancer diagnosis, therapy, as a vehicle for drug delivery, diagnostic carrier for tumor imaging, and cancer immunotherapy. We shall also briefly reflect upon the recent advancements of the exosome-liposome hybrids in cancer therapy. Finally, we put forward future directions for the use of exosome/liposome and/or hybrid nanocarriers for accurate diagnosis and personalized therapies for cancers.

Keywords: drug delivery; exosome-liposome hybrid; extracellular vesicles (EVs); immunotherapy; liposome; liquid biopsy.

Fig. 1. Exosomes are formed from late endosomes and are formed by the inward budding of the multivesicular body (MVB) membrane.

The ESCRT machinery is critical for the formation of exosomes. During exosome biogenesis, ESCRT-independent functions are played by nSMase2 and members of the RAB GTPase family. Micro-vesicles are formed by the plasma membrane budding, which is controlled by cytoskeletal and regulatory proteins. Phosphatidylserine (PS) and phosphatidylethanolamine (PEA) are homogeneously expressed throughout their membrane (PE). The development of apoptotic bodies occurs during the event of apoptosis. These vesicles are irregular in size and form, and they comprise nuclear fractions and cytoplasmic organelles, as well as phosphatidylserine in large quantities on their membrane. Exosomes are internalized by cells directly through a variety of pathways, including by phagocytosis, plasma membrane fusion, macropinocytosis, and endocytosis. Exosomes may have a significant impact on cellular processes by participating in genetic/protein transition, transcriptional control, and post-transcriptional regulation. Alternatively, exosomes can fuse with the lysosomes for degradation.

Fig. 2. Timeline: Breakthroughs in exosome and liposome research.

The timeline and significant milestones in the progress of extracellular vesicle (EV) and liposome research in cancer drug delivery, detection and therapy. siRNA small interfering RNA, CRISPR clustered regularly interspaced short palindromic repeats.

Fig. 3. Graphical presentation of the liposome as a theranostic nano-platform.

Left-hand panel: liposomes are classified depending on their size and lamellarity. Right-hand panel: the schematic shows the many permutations that may be utilized to create multifunctional liposomes, which can subsequently be employed for theranostic applications such as cargo transport, tumor targeting, and diagnostics. a Liposomes with stimuli-responsive structures. b Surface changes, including PEGylated liposomes, to create targeted liposomes. c Tumor screening diagnostics applications. d Hybrids of exosomes and liposomes for tumor targeting. Reproduced from Madamsetty et al. [144]. DOI: 10.1016/C2019-0-02790-2 Copyright © 2021 Elsevier Inc. In Press.

Fig. 4. Liquid biopsy workflow for cancer diagnosis and treatment.

First panel showing exosome and EV release sites. Tumor-derived exosomes and EVs can be isolated from different types of bodily fluids. Second panel showing different methods for exosome isolation from bodily fluid and cell culture media. Third panel shows different methods used for the analysis of exosome biophysical properties and the molecular profiling of cargo. The available information can be used for diagnosis and treatment.

Fig. 5. Schematic showing potential pro-tumorigenic role of tumor-derived exomes (TEX) in cancer.

This figure is inspired by Zhang et al. [93].

Fig. 6. Schematic diagram showing the process to engineer the exosome-liposome hybrids.

Figure inspired from Sato et al. [118].